Regulation of Retinal Inflammation by Rhythmic Expression of MiR-146a in Diabetic Retina

May 29, 2014Investigative ophthalmology & visual science

Daily cycles of MiR-146a control eye inflammation in diabetes

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Abstract

Diabetes led to a 1.6-fold decrease in ICAM-1 expression when miR-146a was mimicked in human retinal endothelial cells.

Diabetes inhibited the daily rhythm of the negative clock gene per1 and enhanced the positive clock gene bmal1 in the retina.
Daily expression patterns of miR-146a and its target gene IRAK1 were disrupted in diabetic retinas.
Loss of rhythmic miR-146a expression was linked to increased levels of inflammatory markers ICAM-1, IL-1β, and VEGF.
Retinal endothelial cells from diabetic donors exhibited reduced amplitude of miR-146a and increased amplitude of IRAK1 and ICAM-1.
Manipulating miR-146a levels in human retinal endothelial cells significantly altered ICAM-1 expression, suggesting its role in inflammatory responses.

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PURPOSE: Chronic inflammation and dysregulation of circadian rhythmicity are involved in the pathogenesis of diabetic retinopathy. MicroRNAs (miRNAs) can regulate inflammation and circadian clock machinery. We tested the hypothesis that altered daily rhythm of miR-146a expression in diabetes contributes to retinal inflammation.

METHODS: Nondiabetic and STZ-induced diabetic rats kept in 12/12 light/dark cycle were killed every 2 hours over a 72-hour period. Human retinal endothelial cells (HRECs) were synchronized with dexamethasone. Expression of miR-146a, IL-1 receptor-associated kinase 1 (IRAK1), IL-1β, VEGF and ICAM-1, as well as clock genes was examined by real-time PCR and Western blot. To modulate expression levels of miR-146a, mimics and inhibitors were used.

RESULTS: Diabetes inhibited amplitude of negative arm (per1) and enhanced amplitude of the positive arm (bmal1) of clock machinery in retina. In addition to clock genes, miR-146a and its target gene IRAK1 also exhibited daily oscillations in antiphase; however, these patterns were lost in diabetic retina. This loss of rhythmic pattern was associated with an increase in ICAM-1, IL-β, and VEGF expression. Human retinal endothelial cells had robust miR-146a expression that followed circadian oscillation pattern; however, HRECs isolated from diabetic donors had reduced miR-146a amplitude but increased amplitude of IRAK1 and ICAM-1. In HRECs, miR-146a mimic or inhibitor caused 1.6- and 1.7-fold decrease or 1.5- and 1.6-fold increase, respectively, in mRNA and protein expression levels of ICAM-1 after 48 hours.

CONCLUSIONS: Diabetes-induced dysregulation of daily rhythms of miR-146a and inflammatory pathways under miR-146a control have potential implications for the development of diabetic retinopathy.

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Regulation of Retinal Inflammation by Rhythmic Expression of MiR-146a in Diabetic Retina

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